Methods for the preparation of biphenyl isoxazole sulfonamides

Abstract

Methods for the preparation of biphenyl isoxazole sulfonamides and intermediates thereof. The present invention also relates to the novel intermediates prepared by these methods. The biphenyl isoxazole sulfonamides prepared by the present methods are endothelin antagonists useful, inter alia, for the treatment of hypertension.

What is claimed is: 
     
       1. A method for the preparation of a biphenyl sulfonamide of the following formula I: ##STR50## where the phenyl rings of the biphenyl group may independently be unsubstituted or substituted with one or more substituent groups, enantiomers and diastereomers, and salts thereof, wherein: one of X and Y is N and the other is O;   R 3  and R 4  are each directly bonded to a ring carbon and are each independently (a) hydrogen;   (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z 1 , Z 2  and Z 3  ;   (c) halo;   (d) hydroxyl;   (e) cyano;   (f) nitro;   (g) --C(O)H or --C(O)R 5  ;   (h) --CO 2  H or --CO 2  R 5  ;   (i) --Z 4  --NR 6  R 7  ;   (j) --Z 4  --N(R 10 )--Z 5  --NR 8  R 9  ; or   (k) R 3  and R 4  together may also be alkylene or alkenylene, either of which may be substituted with Z 1 , Z 2  and Z 3 , completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached;     R 5  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z 1 , Z 2  and Z 3  ;   R 6 , R 7 , R 8 , R 9  and R 10  are each independently (a) hydrogen; or   (b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z 1 , Z 2  and Z 3  ; or     R 6  and R 7  together may be alkylene or alkenylene, either of which may be substituted with Z 1 , Z 2  and Z 3 , completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; or any two of R 8 , R 9  and R 10  together are alkylene or alkenylene, either of which may be substituted with Z 1 , Z 2  and Z 3 , completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;   Z 1 , Z 2  and Z 3  are each independently (a) hydrogen;   (b) halo;   (c) hydroxy;   (d) alkyl;   (e) alkenyl;   (f) aryl;   (g) aralkyl;   (h) alkoxy;   (i) aryloxy;   (j) aralkoxy;   (k) heterocycle, substituted heterocycle or heterocyclooxy;   (l) --SH, --S(O) n  Z 6 , --S(O) m  --OH, --S(O) m  --OZ 6 , --O--S(O) m  --Z 6 , --O--S(O) m  OH or --O--S(O) m  --OZ 6  ;   (m) oxo;   (n) nitro;   (o) cyano;   (p) --C(O)H or --C(O)Z 6  ;   (q) --CO 2  H or --CO 2  Z 6  ;   (r) --Z 4  --NZ 7  Z 8  ;   (s) --Z 4  N(Z 11 ) --Z 5  --H;   (t) --Z 4  --N(Z 11 )--Z 5  --Z 6  ; or   (u) --Z 4  --N(Z 11 )--Z 5  --NZ 7  Z 8  ;     Z 4  and Z 5  are each independently (a) a single bond;   (b) --Z 9  --S(O) n  --Z 10  --;   (c) --Z 9  --C(O)--Z 10  --;   (d) --Z 9  --C(S)--Z 10  --;   (e) --Z 9  --O--Z 10  --;   (f) --Z 9  --S--Z 10  --;   (g) --Z 9  --O--C(O)--Z 10  --; or   (h) --Z 9  --C(O)--O--Z 10  --;     Z 6  is alkyl; alkyl substituted with one to three groups selected from halogen, aryl, aryloxy and alkoxy; alkenyl; alkynyl; cycloalkyl; cycloalkyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkoxyaryl; cycloalkyl to which is fused a benzene ring; aryloxy substituted with one or two halogens; cycloalkylalkyl; cycloalkenyl; cycloalkenylalkyl; aryl; aryl substituted with methylenedioxy or one to four groups selected from alkyl, dialkylamino, cyano, halogen, trihaloalkyl, alkoxy and trihaloalkoxy; or heterocycle or substituted heterocycle;   Z 7  and Z 8  are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, or Z 7  and Z 8  together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached;   Z 9  and Z 10  are each independently a single bond, alkylene, alkenylene or alkynylene;   Z 11  is (a) hydrogen; or   (b) alkyl, alkyl substituted with one, two or three halogens, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl; or any two of Z 7 , Z 8  and Z 11  together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;       each m is independently 1 or 2; and   each n is independently 0, 1 or 2; comprising the steps of: (a) contacting a pinacol ester of the formula II or salt thereof: ##STR51## where the phenyl ring of said formula II may be further substituted, and where "prot" denotes a nitrogen-protecting group, with a halophenyl compound of the formula III or salt thereof: ##STR52## where the phenyl ring of said formula III may be further substituted, in the presence of a palladium(0) catalyst and, optionally, a base, to form a nitrogen-protected compound of the formula IV or salt thereof: ##STR53## where the phenyl rings of the biphenyl group may independently be unsubstituted or substituted with one or more substituent groups; and     (b) deprotecting the nitrogen of said compound of the formula IV or salt thereof to form said compound of the formula I or salt thereof.   
     
     
       2. The method of claim 1, for the preparation of a compound of the following formula Ia: ##STR54## and enantiomers and diastereomers, and salts thereof, wherein: R 1  and R 2  are each directly bonded to a ring carbon and are each independently selected from those groups (a) through (j) recited above for R 3  and R 4  ; R 11 , R 12 , R 13  and R 14  are each independently (a) hydrogen;   (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z 1 , Z 2  and Z 3 ,   (c) heterocycle, substituted heterocycle or heterocyclooxy;   (d) halo;   (e) hydroxyl;   (f) cyano;   (g) nitro;   (h) --C(O)H or --C(O)R 5  ;   (i) --CO 2  H or --C 2  R 5  ;   (j) --SH, --S(O) n  R 5 , --S(O) m  --OH, --S(O) m  --OR 5 , --O--S(O)m-OR 5 , --O--S(O) m  OH or --O--S(O) m  --OR 5  ;   (k) --Z 4  --NR 6  R 7  ; or   (l) --Z 4  --N(R 10 )--Z 5  --NR 8  R 9  ;     J is O, S, N or NR 15  ;   K and L are N or C, provided that at least one of K or L is C;   R 15  is hydrogen, alkyl, hydroxyethoxy methyl or methoxyethoxy methyl; and   is 0 or an integer from 1 to 2; comprising the steps of: (a) contacting a pinacol ester of the formula IIa or salt thereof: ##STR55## with a halophenyl compound of the formula IIIa or salt thereof: ##STR56## in the presence of a palladium(0) catalyst and, optionally, a base, to form a nitrogen-protected compound of the formula IVa or salt thereof: ##STR57## (b) deprotecting the nitrogen of said formula IVa compound or salt thereof to form said compound of the formula Ia or salt thereof.     
     
     
       3. The method of claim 2, wherein said palladium(0) catalyst is a palladium (II) salt which is contacted with triphenylphosphine. 
     
     
       4. The method of claim 3, wherein said palladium (II) salt is palladium acetate. 
     
     
       5. The method of claim 2, wherein said base is aqueous potassium carbonate or sodium carbonate. 
     
     
       6. The method of claim 2, wherein "prot" is methoxyethoxymethyl or 2-ethoxyethyl. 
     
     
       7. The method of claim 2, wherein the halo group in said compound of the formula IIIa or salt thereof is bromo, chloro, or iodo. 
     
     
       8. The method of claim 2, wherein said compound of the formula Ia or salt thereof is crystallized from solution subsequent to step (b). 
     
     
       9. The method of claim 2, wherein residual palladium is removed subsequent to step (a) by use of a chelating agent. 
     
     
       10. The method of claim 2, wherein said compound of the formula IIa or salt thereof is N- (2-methoxyethoxy)methyl!-N-(3,4-dimethyl-5-isoxazolyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfanamide, said compound of the formula IIIa or salt thereof is 2-(4-iodophenyl)oxazole, and said compound of the formula Ia or salt thereof is N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)  1,1'-biphenyl!-2-sulfonamide.